The long-term goal of this project is a detailed understanding of how neural cell fates are specified in the ectoderm of developing animals. In all species that have been studied, this process depends on the activity of "proneural" genes, which encode a distinctive family of basic helix-loop-helix transcriptional activator proteins. Our recent preliminary studies in Drosophila have revealed the existence of novel modes of regulation of the proneural genes (both transcriptional and post-transcriptional), and have defined a set of very interesting genes that are expressed downstream of the proneurals during adult peripheral nervous system (PNS) development. This project has three major objectives, all focused on the regulation and function of proneural gene activity: (1) Investigate the functional relationship between proneural genes and Notch-mediated lateral inhibition. (2) Investigate novel modes of post-transcriptional regulation of proneural gene activity. (3) Investigate the function and regulation of genes that act downstream of proneural genes. The Drosophila adult PNS (where the existence of the proneural genes was first revealed genetically-nearly a century ago) remains, we think, a particularly advantageous venue in which to study these key cell fate determinants. Nevertheless, the results of this project may be expected to have significance well beyond the particular setting of the fly PNS. Of particular importance is the observation that a broad spectrum of human tumors with a "neuroendocrine" phenotype are associated with strong overexpression of proneural genes, including small cell lung cancer (the most lethal form of lung cancer) and neuroblastoma (an aggressive childhood cancer). By elucidating both transcriptional and post-transcriptional mechanisms that normally regulate proneural gene activity negatively, our work may offer important insight into the pathogenesis of these diseases. By helping to illuminate shared mechanisms of neurogenesis, we also expect to contribute substantially to our broad understanding of how animals build their nervous systems.